Analgesia producing benzazocines



United I States Patent ANALGESIA PRODUCING BENZAZOCINES Sydney Archer, Bethlehem, N.Y., assignor to Sterling Drug Inc, New York, N.Y., a corporation of Delaware No Drawing. Filed Jan. 16, 1963, Ser. No. 251,721 9 Claims. (Cl. 167-65) This application is a continuation-impart of my prior co-pending application Serial No. 72,844, filed December 1, 1960, and of my prior co-pending application Serial No. 239,777, filed November 23, 1962.

This invention relates to derivatives of 1,2,3,4,5,6-hexasia, thus relieving pain.

My new compounds are, in one group, the 1,2,3,4,5,6- hexahydro 3 (Z)-6-(R )-l1-(R )-8-(R -O)-2,6-methano- S-benzazocines having the structural formula Formula I and, in another group, the 1,2,3,4,5,6-hexahydro-3-(Y)- 6,1l-dimethyl-8-(R -O-)-2,6-methano-3-benzazocines having the structural formula CH2CH /10 1 Formula II In each of Formulas I and II, R is a member of the group consisting of hydrogen, methyl, lower alkanoyl, and pyn'dinecarbonyl. When R is lower alkanoyl, it preferably contains 1-6 carbon atoms, including for example formyl, acetyl, .propionyl, butyroyl, isobutyroyl, and caproyl. When R is pyridinecarbonyl, it includes 2-pyridinecarbonyl or picolinoyl, 3-pyridinecarbonyl or nicotinoyl, and 4-pyridinecarbonyl or isonicotinoyl.

In Formula I, one of R and R is ethyl and the other is a member of the group consisting of hydrogen, methyl, and ethyl; and Z is lower alkenyl containing 3-6 carbon atoms. The lower alkenyl group Z includes the monovalent lower molecular weight unsaturated aliphatic hydrocarbon radicals containing a double bond, and having 3-6 carbon atoms, for example, -CH CH=CH CH -C(CH )=CH CH(CH )CH=CH CH(CH )CH:C(CH and the like.

In Formula II, Y is lower alkenyl containing 4-6 carbon atoms. The group Y includes the monovalent lower molecular weight unsaturated aliphatic hydrocarbon radhydro 2,6 methano 3 benzazocine, to the preparation ice icals containing a double bond and having 4-6 carbon atoms, for example,

hexahydro-3 (Z -6- R -1 1- (R -8-hydroxy-2,6-methano- 3-benzazocines of Formula I and the new l,2,3,4,5,6- hexahydro-3-(Y)-6,1l-dimethyl 8-hydroxy-2,6-methano- 3-benzazocines of Formula II have amphoteric properties; and therefore for a given compound, the particular molecular species which will predominate will depend on the pH of the environment. Thus, in strongly acidic media, the amino nitrogen will be .protonated, and the predominant molecular species will be an acid-addition salt. On the other hand, in strongly alkaline media, the predominant molecular species of the S-hydroxy compounds, i.e., when R is hydrogen, will be that of a phenolate ion; and under pH conditions intermediate between these extremes, the proportion of the undissociated molecular species will increase to reach a maximum as the isoelectric point is approached, the form which is isolable at the isoelectric point being conveniently termed the isoelectrin form.

My new compounds can exist in stereochemically isomeric forms, that is, optical isomers and geometric isomers. If desired, the isolation or the production of a particular stereochemical form can be accomplished by application of the general principles known in the prior art.

The acid-addition salt forms and the phenoxide forms of my new compounds are useful not only as antagonists of certain strong analgesic agents and as analgesic agents, as above-indicated, but are also useful for characterizing and identifying purposes, and in isolation or purification procedures. Moreover, the acid-addition salts and the phenoxides are sources of the free base forms and the isoelectric forms, by reaction with bases or acids, respectively, and accordingly all of the acid-addition salts and the phenoxides, regardless of considerations of solubility, toxicity, physical form, or the like of a particular compound are useful for the purposes of my invention.

It will be appreciated from the above that if one or more of the characteristics, such as solubility, molecular weight, physical appearance, toxicity, or the like of a given free base, isoelectric, phenoxide, or acid-addition salt form of a particular compound render that form unsuitable for the purpose at hand, it can be readily converted to another, more suitable form.

The new compounds of my invention wherein R in Formulas I and II is hydrogen can be conveniently prepared in their isoelectric forms by N-alkylating the respective corresponding secondary amines. Thus, the 8- hydroxy compounds of Formula I are obtained by heating a l,2,3,4,5,6-hexahydro 6-(R 11-(R )-8-hydroXy- 2,6-methano-3-benzazocine with an alkylating agent having the structural formula Z-An, and the 8-hydroxy compounds of Formula II are obtained by heating a 1,2, 3 ,4,5,6-hexahydro-3 (Y) -6, l 1-dimethyl-8-hydroxy-2,6-

the formula YAn, where Z and Y have the same meanings indicated hereinabove and An in each instance is the anion of a strong organic or inorganic acid, for instance a reactive halide or an arylsulfonate, e.g., a tosylate. These alkylations are carried out in the presence of an acid-absorbing medium, for instance an alkali metal carbonate or bicarbonate, for instance sodium bicarbonate, and preferably a suitable reaction medium is used, such as a lower alkanol, for instance methanol or ethanol, or an N,N-(di-lower alkyl)-lower allcanamide, 'for instance N,N-dimethylformamide or N,N-dimethylacetamide.

The new 8-methoxy and 8-acyloxy compounds of Formulas I and II are conveniently obtained by appropriate etherification and esterification, respectively, of the respective corresponding 8-hydroxy compounds, using any of the conventional prior art methods suitable for the etherification and esterification of phenols. Thus, for instance, the 8-methoxy compounds are obtained either directly by treatment of the S-hydroxy compounds of Formulas I and II with diazomethane, .or the S-hydroxy compounds of Formulas III and IV hereinbelow are treated with diazomethane or with dimethyl sulfate to produce the S-methoxycompounds of Formulas III and 1V and the latter are reduced with lithium aluminum hydride to produce the 8-methoxy compounds of Formulas I and II, respectively. Treatment of the 8-hydroxy compounds of Formulas I and II with the acid anhydride or acid chloride of a lower alkanoic acid or a pyridinecarboxylic acid yields the corresponding 8- (lower alkanoyloxy) or S-(pyridinecarbonyloxy) compounds of Formulas I and II.

The following is another method suitable for preparing the S-hydroxy and 8-methoxy compounds of Formulas I and II wherein the carbon atom of Z linked to the nitrogen atom in Formula- I, or the carbon atom of Y linked to the nitrogen atom in Formula II, is unbranched, so that a .-CH;; group in Z or Y, as the case may be, is adjacent to the nitrogen atom. A 1,2,3, 4,5,6 hexahydro-6-(R )-l 1-(R )-8-hydroxy or methoxy- 2,6 methano-3-benzazocine or a l,2,3,4,5,6-hexahydro- 6,11-dimethyl-8-hydroxy or methoxy-2,6-methano-3-benzazoci ne is acyiated by treatment with one or two molecular equivalents of an acid halide or acid anhydride of an acid having the formula Z'COOH in preparing the Formula I series and Y'COOI-I in preparing the Formula II series, Z being lower alkenyl containing 2-5 carbon atoms and Y being lower alkenyl containing 35 carbon atoms. The resulting amide or esteramide derivative is a 1,2,3,4,5,6-hexahydr-o-3-(Z--CO)-6-(R 11-(R )-8-hydroxy or methoxy-2,6-methano3-benzazocine having the structural formula I Formula III or is a l,2,3,4,5,6-hexahydro-3-(Y-CO)-6,ll-dirnethyl-8-hydroxy or methoxy-2,6-methano3-benzazocine having the structural formula Formula IV R R Z, and Y in Formulas III and IV have the same meanings hereinbefore indicated. When one molecular equivalent of the acylating agent is used, R in each of Formulas III and IV is a member of the group consisting of hydrogen and methyl; and R is Z'CO-- in Formula III and is Y'-CO in Formula IV when an 8- hydroxy starting material is acylated with two molecular equivalents of the acylating agent. Treatment of the compound of Formula III with a reducing agent such as lithium aluminum hydride effective to reduce the IV, in some instances both N- and O-acylation may occur to yield a mixture of the 3-acyl and 3-acyl-8-acyloxy compounds, but this is of no consequence in the overall process, because in the reduction step both the amides and the ester-amides of Formulas III and IV when R is either hydrogen or acyl are converted to the 1,2,3,4, 5,6-hexahydro-3-(Z'-CH -)-6-(R )-l1-(R )-8-hydroxy- 2,6-methano-3-benzazocine and the l,2,3,4,5,6-hexahydro- 3 (Y-CH 6,1l-dimethyl-S-hydroxy-2,6-methano- 3-benzazocines, respectively.

The acid-addition salt forms of my compounds are prepared from any organic acid, inorganic acid (including organic acids having an inorganic group therein), or organo-rnetallic acid as exemplified by organic monoand poly-carboxylic acids such as found, for example, in Beilsteins Organische Chemie,,4tl1 cd., volumes III, IV, IX, X, XIV, XVII, XIX, XXI, XXII, and XXV; organic monoand polysulfonic acid-sulfinic acids such as found, for example in Beilstein, volumes VI, XI, XVI, and XXII; organic phosphonic and phosphinic acids such as found, for example in Beilstein, volumes XI and XVI; organic acids or arsenic and antimony such as found, for example, in Beilstein, volume XVI; organic heterocyclic carboxylic, sulfonic, and sulfinic acids such as i found, for example, in Beilstein, volumes XVIII, XXII, and XXV; acidic ion-exchange resins; and inorganic acids of any acid forming element or combination of elements such as found in Mellor, Comprehensive Treatise on Inorganic and Theoretical Chemistry, Longmans, Green and Co., New York, N.Y., volumes I-XVI. In addition, other salt-forming compounds which are acidic in their chemical properties but which are not generally considered as acids in the same sense as carboxylic or sulfonic acids are also considered to be among the numerous acids which can be used to prepare the acidaddition salt forms of the compounds of this invention. Thus there are also included acidic phenolic compounds such as found, for example, in volume VI of Beilstein, acidic compounds having activated or acidic hydrogen atoms, as for example, picrolonic acid, or barbituric acid derivatives having an acidic proton such as found,

for example, in Cox et al., Medicinal Chemistry, vol. IV, John Wiley and Sons, Inc., New York, NY. (1959). Also included as salt forming agents are so-called- Lewis acids which lack a pair of electrons in the outer electron shell and react with basic compounds having an unshared pair of electrons to form salts, for example boron trifluoride.

Representative acids for the formation of the acld-addltion salts include'formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, trifluoroacetic acid, malic acid, fumaric acid, succinic acid, succinamic acid, glutamic acid, tartaric acid, oxalic acid, pyromucic acid, citric acid, lactic acid, glycolic acid, gulconic acid, succharic acid, ascorbic acid, penicillin, benzoic acid, phthalic acid, salicylic acid, 3,5-dinitrobenzoic acid, anthranilic acid, cholic acid, 2-pyridinecarboxylic acid, pamoic acid, 3-hydroxy-2- naphthoic acid, picric acid, quinic acid, tropic acid, 3-indoleacetic acid, barbituric acid, sulf-amic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, butylarsonic acid, methanephosphonic acid, acidic resins, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, arsenic acid, and the like. The acid-addition salts with lactic acid and with ethanesulfonic acid, for example, are water-soluble and are especially suitable forms for using my new compounds as therapeutic agents.

The acid-addition salts are prepared in conventional fashion, for instance either by direct mixing of the acid and the free base or isoelectric form or, when this is not appropriate, by dissolving either or both of the acid and the free base or isoelectric for-m separately in water or an organic solvent and mixing the two solutions, or by dissolving -both the acid and the free base or isoelectric form together in a solvent. The resulting acid-addition salt is isolated by filtration, if it is insoluble in the reaction medium, or by evaporation of the reaction medium to leave the acid-addition salt as a residue. The acid moieties or anions in these salt formsare in themselves neither novel nor critical and therefore can be any acid anion or acid-like substance capable of salt formation with the free base or isoelectric forms of my compounds.

The phenolate .form of my new 8-hydroxy compounds of Formulas I and II is readily obtained for example by treatingthe isoelectric form with a strong alkali, such as sodium hydroxide. The alkali metal phenolates are watersoluble.

The 1,2,3,4,5,6 hexahydro 6,11 dimethyl 8 hydoxy-2,6-methano-3-benzazocine used as a starting material in preparing the compounds of Formula II is a known compound. The 1,2,3,4,5,6-hexahydro-6-(R )-11-(R )-8- hydroxy-2,6-methano-3-benzazocine starting materials for the preparation of the compounds of Formula I can be obtained by application of known procedures. Thus, a 3-(R )-4-(R )-pyridine methiodide is interacted with pmethoxybenzylmagnesium chloride; the resulting N-methyl 2 (p-methoxybenzyl) 3 (R 4 (R 1,2- dihydropyridine is reduced with sodium borohydride or by catalytic hydrogenation to produce an N-methyl-Z-(pmethoxybenzyl) 3 (R 4 (R 1,2,5,6 tetrahydropyridine; and this latter product is heated with an appropriate cycli'zing agent, such as concentrated hydrobromic or phosphoric acid to yield a 1,2,3,4,5,6-hexahydro 3 methyl 6 (R -11 (R 8 hydroxy 2,6- methano-3-benzazocine. By acetylating the 8-hydroxyl group in this cyclization product by treatment with acetic anhydride and treatment of the resulting 8-acetoxy compound with cyanogen bromide, there is produced a 1,2,3,4, 5,6 hexahydro 3 cyano 6 (R 11 (R 8- acetoxy-2,6-methano-3-benzazocine which, by heating with dilute hydrochloric acid, is converted to the desired 1,2,3, 4,5,6 hexahydro 6 (R 11 (R 8 hydroxy 2,6- methano-3-benzazocine. This series of reactions is illustrated in part E of Example 1 hereinbelow.

The alkylating agents XAn and Y-An used in the alkylation procedures for preparing my compounds are likewise readily obtainable by known methods; for instance, in one method the corresponding alcohol having the formula Z--OH or YOH is esterified with a strong organic or inorganic acid having the formula HAn.

By alternative system of nomenclature, the compounds of this invention are designated as benzomorphan derivatives; thus, the compounds of Formula I can be named as 2-(Z) -2'-(R -O-)-5-(R -9-(R -6,7-benzomorphans, and the compounds of Formula II can be named as 2-(Y)-2'- (R -O-) -5 ,9-dimethyl-6,7-benzomorphans.

The structures of the compounds of this invention followed from the methods of synthesis which were used and from the elementary analyses of the products ob tained.

My invention is illustrated by the following examples without, however, being limited thereto.

Example 1 .-1 ,2,3,4,5 ,6 -hexahydr0-3-ally l-6 -ethyl-1 1- metlzyl-8-hydroxy-2,6-methan0-3-benzaz0cine A. A mixture of 2.62 g. of 1,2,3,4,5,6-hexahydro-6- ethyl 11 methyl 8 hydroxy 2,6 methano 3- benzazocine, 1.37 g. of allyl bromide, 40 ml. of methanol, and 1.32 g. of sodium bicarbonate was stirred and refluxed for approximately six hours. The reaction mixture was then filtered to remove a small amount of solid. Thefiltrate was concentrated under reduced pressure and then extracted with chloroform. The chloroform extract was filtered and the filtrate was concentrated to yield a syrupy residue. This syrup solidified when triturated with diethyl ether, and the solid was collected on a filter. The solid thus obtained weighed 2.4 g. and melted at 150-157 C. This product was dissolved in acetone and the resulting solution was filtered to remove a small amount of amorphous solid. The filtrate was concentrated and then chilled, and the solid which separated from solution was collected on a filter. There was thus obtained 1.5 g. of solid which melted at 150-162 C. It was dissolved in ether and the solution was filtered. By evaporation of the filtrate there was obtained 1.1 g'. of off-white solid which melted at 163-165" C. This product was 1,2,3,4, 5,6 hexahydro 3 allyl 6 ethyl 11 methyl 8- hydroxy-2,6-methano-3-benzazocine (Formula I:

R =C H R2'=CH3 R =H), having the molecular formula C H NO.

B. Interaction of 1,2,3,4,5,6-hexahydro-3-allyl-6-ethyl 11 methyl 8 hydroxy 2,6 methano 3 benzazocine with diazomethane yields 1,2,3,4,5,6-hexa-hydro-3-a1lyl-6- ethyl 11 methyl 8 methoxy 2,6 methano 3 benzazocine (Formula I:

C. Interaction of 1,2,3,4,5,6-hexahydro-3-allyl-6-ethyl- 11 methyl 8 -'hydroxy 2,6 methano 3 benzazocine with acetic anhydride yields 1,2,3,4,5,6-hexahydro-3-allyl- 6 ethyl 11 methyl 8 acetoxy 2,6 methano 3- benzazocine (Formula I:

D. Interaction of 1,2,3,4,5,6-hexahydro-3-a1lyl-6-ethyl- 11 methyl 8 hydroxy 2,6 methano 3 benzazocine with nicotinoyl chloride yields l,2,3,4,5,6-hexahydro-3- allyl 6 ethyl 11 methyl 8 nicotinoyloxy 2,6- methano 3 benzazocine-Formula I:

E. The following procedure was employed for preparing the 1,2,3,4,5,6-hexahydro-6-ethyl-11-methyl-8-hydroxy-2,6-methano-3-benzazocine starting material in the procedure described in part A above.

A solution of 151 g. of p-methoxybenzyl chloride in 925 ml. of anhydrous diethyl ether was added slowly over a periodof approximately three hours to a refluxing mixture of 1725 ml. of anhydrous diethyl ether, 50.5 g. of magnesium turnings, and 42.3 g. of magnesium powder. The liquid in the reaction mixture was then siphoned away from the solid, which remained at the bottom of the reaction vessel, into a solution of 127 g. of 3-.methyl-4-ethylpyridine methiodide (prepared by interaction otf e'quimolecular amounts of 3-methyl-4-ethyl pyridine and methyl iodide) in 925 ml. of diethyl ether. The resulting mixture was stirred for approximately one hour, and the reaction mixture thus obtained was poured into a mixture of ice and water having one-half pound of ammonium chloride dissolved therein. The mixture, which had a lower, aqueous layer and an upper, ethereal layer, was made basic by addition of concentrated ammonium hydroxide. The ethereal layer was then separated from the aqueous layer and dried. The dry ethereal solution was concentrated and the resulting residue, which contained N methyl 2 (p methoxyibenzyl) 3- methyl-4-ethyl-1,Z-dihydropyridine, was dissolved in 430 ml. of methanol. To this solution there was gradually added over a period of fifteen minutes 9.3 g. of sodium borohydride in ml. of ice water, the temperature of the resulting reaction mixture being kept below 40 C.

was then extracted with diethyl ether.

pressure.

by means of an ice-bath during the addition. The reaction mixture was stirred at room temperature for onehalf hour more, and then the methanol was distilled from the reaction mixture, leaving a residue containing N methyl 2 (p methoxybenzyl) 3 methyl -'4- ethyl- 1,2,5,6-tetrahydropyridine.

The foregoing procedure was repeated, using the same amounts of reactants and other materials with the exous layer being discarded, and the ethereal layer was extracted with water to which had been added 80 ml. of concentrated hydrochloric acid. The aqueous extract was made basic by addition of potassium carbonate and After being dried, the ether extract was fractionally distilled under reduced The fraction (I) distilling in the range of 106 C. at 0.2 mm. pressure to 136 C. at 0.5 mm. pressure weighed 127.1 g. and consisted of almost pure N methyl 2 (p methoxybenzyl) 3 methyl 4- ethyl-l,2,5,d-tetrahydropyridine. The fraction (II) dis tilling at 136-147 C. at 0.5 mm. pressure weighed 15.9 g.; a substantial proportion of this fraction was an additional yield of N-methyl-2-(Ip-methoxybenzyl)-3-methyl- 4-ethyl-1,2,5,6-tetrahydropyridine.

A mixture of 127 vg. of N methyI-Z-(p-methoxybenzyD- 3-methyl-4-ethyl-l,2,5,6-tetrahydropyridine and 1450 ml. of concentrated (4-8 percent) hydrobro-mic acid was refluxed for approximately twenty-four hours. The reaction mixture was mixed with decolorizing charcoal and filtered. The filtrate was concentrated and then water was added, which caused separation of an oily layer. Concentrated ammonium hydroxide was added to the mixture, and the solid which formed was collected on a filter. The tan product thus collected weighed 47.8 g. and melted at 23 l-246 C. This solid was suspended in 100 ml. of ethanol, and the suspension was heated, then cooled, and filtered. The pale yellow solid thus collected weighed 37.4 g. and melted at 246-251 C. This product was 1,2,3,4,5,6-hexahydro-3-methyl-6-ethyl- 1 l-methyl 8-hydroxy-2,6-:methano-3 #benzazocine.

A mixture of 40.8 g. of 1,2,3,4,5,6-hexahydro-3-methyl- 6 ethyl 11 methyl 8 hydroxy 2,6 met-hauo 3- benzazocine and 120 ml. of acetic anhydride was heated on a steam bath for approximately three hours. The reaction mixture was then concentrated, ether was added, and the. resulting mixture was added to ice in a separatory funnel. The ethereal layer was collected, washed with a solution of 80 g. of potassium hydroxide in 80 ml. of water, and concentrated under reduced pressure on a steam bath. The syrupy residue thus obtained, which was 1,2,3,4,5,d-hexahydro-3-methyl-6-ethyl-l1- methyl-S-acetoxy-Z,6-methano 3 benzazocine, weighed 44.8 g. This product was dissolved in 125 ml. of chloroform and this solution was added to a solution of 18.6 g. of cyanogen bromide in 90 ml. of chloroform at room temperature. The resulting mixture was refluxed for two and one-half hours. The reaction mixture was then concentrated under reduced pressure to yield a residue which consisted chiefly of 1,2,3,4,5,6-hexahydrosolid crystalline product thus collected was dissolved in approximately 200 ml. of hot water, decolorizing charcoal was added and the solution was filtered while hot.

Concentrated ammonium hydroxide was added to the solution, which was then cooled. The solid which separated from solution was collected on a filter and dried. A further crop of solid was obtained by working up the oily material mentioned above. The two crops were combined, ground finely, and heated in suspension in ml. of methyl alcohol. The suspension was cooled and filtered. The solid thus collected weighed 16.7 vg. and melted at 245-250 C. with decomposition. This prodnot was 1,2,3,4,5,6-hexahydro-6-ethy1-1lrnethyl-8-hy droxy-2,6-methano-3-benzazocine.

Example 2.1,2,3,4,5,6-hexahydr03-allyl-6-elhyl- 8-hydroxy-2,6-metlzano-3-benzazocine Following the procedure described in Example 1 here inabove but substituting 1,2,3,4,5,6 hexahydro-6-ethyl-8- hydroxy-2,6-n1ethano-3-benzazocine in molar equivalent amount for the corresponding 6-ethyl-l1-met-hyl compound used in that example, there is obtained 1,2,3,4,5,6- hexahydro- 3 allyl 6 ethyl 8 hydroxy 2,6- methano-3- benzazocine (Formula I:

Example 3.-1,2,3,4,5,6-hexahydr0-3-allyl-11-ethyl-8- hydroxy-2,6-methano -3-benzazocine Following the procedure described in Example 1 hereinabove but substituting l,2,3,4,5,6-hexahydro-ll-ethyl-S- hydroxy-2,6-methano-3-benzazocine in molar equivalent amount for the corresponding 6-ethyl-11-dimethyl compound used in that example, there is obtained 1,2,3,4,5,6- hexahydro 3 allyl 1l-ethyl-S-hydroxy-2,6-methano-3- benzazocine (Formula I: Z:-CH CH=CH Example 4. 1,2,3,4,5,6 hexahydro 3-(3-mezhyl-2-butenyl) 6,11 dimethyl 5 8-hydroxy-2,6-metl1an0-3-benza- Zocine A. A mixture of 8.7 g. of 1,2,3,4,5,6-hexahydro-6,1ldimethyl-8-hydroxy-2,6-methano-3-benzazocine (which is also known as 2'-hydroxy-5,9 dimethyl-6J-benzomorphan), 6.0 g. of 1-bromo-3-methyl-2-butene, 5.0 g. of sodium bicarbonate, and ml. of N,N-dimethylformamide was stirred and refluxed for approximately four and one-half hours. The reaction mixture was then filtered, and the solid on the filter was Washed with ethanol. The filtrate and the wash liquor were combined, concentrated under reduced pressure, and then extracted with chlorofrom. The chloroformextract was concentrated under reduced pressure to yield a syrup which weighed 15.8 g. This syrup was dissolved in 120 ml. of diethyl ether and the resulting solution was filtered to remove approximately one-half gram of a brown amorphous solid. The filtrate was extracted with a mixture of 5 m1. of concentrated hydrochloric acid and 20 ml. of water. To the extract there was added 5 ml. of concentrated ammonium hydroxide solution and ice. A pale tan syrup separated from solution and after stirring, this syrup solidified. The resulting pale tan solid was collected and dried; it weighed 10.6 g. 'After two recrystallizations from a mixture of methyl alcohol and water, with charcoaling, this solid weighed 8.2 g. and melted at 3 cyano 6 --ethyl 11 methyl 8 acetoxy 2,6-

methano-3-benzazocine. To this residue there were added 60 ml. of concentrated hydrochloric acid and 240 ml. of water, and the mixture was refluxed for about twenty-six hours. The reaction mixture was then concentrated under reduced pressure, diethyl ether and a small volume of water were added, and the mixture was filtered. Some oily material passed through the filter into the filtrate; this was recovered and retained. The

147 C. The product thus obtained was 1,2,3,4,5,6 hexahydro 3 (3-methyl-2-butenyl)-6,1l-dimethyl-S-hydroxy-2,6-methano-3-benzazocine (Formula II:

2.80; and when the pH of the 1 percent solution was gradually raised by addition of N/ 10 sodium hydroxide solution, a precipitate formed at pH 5.4.

B. Interaction of l,2,3,4,5,6-hexahydro-3-(3-methyl-2- butenyl) 6,1l-dimethyl-8-hydroxy-2,6-methano-3-benza butenyl) 6,11-dimethyl-8-hydroxy-2,6-methano-3-benzazocine with acetic anhydride yields 1,2,3,4,5,6-hexahydro- 3 (3 methyl 2-butenyl)-6,ll-dimethyl-8aacetoxy-2,6- methano-3-benzazocine (Formula II:

D. Interaction of 1,2,3,4,5,6-hexahydro-3-(3-methyl-2- butenyl) 6,11-dimethyl-8-hydroxy-2,6-methano-3-benzazocine with nicotinoyl chloride and with isonicotinoyl chloride yields, respectively, 1,2,3,4,5,6-hexahydro-3-(3 methyl 2 butenyl) 6,1l-dimethyl-8-nicotinoyloxy-2,6- methano-3-benzazocineFormula II:

and 1,2,3,4,5 ,6 hexahydro-3 -(3-methyl-2-but enyl)-6,l1- dimethyl-8-isonicotinoyloxy-2,6-methano-3 -benzazocine Formula II: Y=CH CH C(CH 2 E. Following the procedure of part A of this example but using the dextro form in one instance, and the levo form in another instance, of l,2,3,4,5,6-hexahydro-6,lldimethyl-8-hydroxy-2,6-methano-3-benzazocine (resolved into the dextro and levo forms using d-tartaric acid) instead of the racemic form used in part A, the respective final products were the dextroand the levo-forms of l,2,3,4,5,6 hexahydro 3-(3-methyl-2-butenyl)-6,1l-dimethyl-8-hydroxy-2,6-methano-3-benzazocine. The dextro compound was obtained in the form of an amber colored powder which melted at l79-l82 C. The levo compound was obtained as white crystals which melted at l76-179 C.

Example 5.],2,3,4,5,6-hexahydr-3-(3-hexenyl) -6,11-

dimethyl-8-hydr0xy-2,6-methan0-3-benzaz0cine Following the procedure described in Example 4 hereinabove but substituting l-bromo-3-hexene in molar equivalent amount for the 1-bromo-3-methyl-2-butene used in that example, there is obtained l,2,3,4,5,6-hexahydro 3-(3-hexenyl)-6,l l-dimethyl-8-hydroxy-2,6-metl1- ano-3-benz azocine (Formula II:

Example 6.1,2,3,4,5,6-hexahydr0-3-(3-hexenyl)-6-ethyl-- 11-methyl-8-hydr0xy-2,6-methan0-3-benzazocine Following the procedure described in Example 1 hereinabove but substituting 1-bromo-3-hexene in molar equivalent amount for the allyl bromide used in that example, there is obtained 1,2,3,4,5,6-hexahydro-3-(3-hex- Example 7.1,2,3,4,5,6-hexahydro-3(3-methyl-2-butenyl) --6-ethyl l1 methyl-8-hydr0xy-2,6-methan0-3- benzazocine A. A mixture of 9.25 g. of 1,2,3,4,5,6-hexahydro-6- ethyl 11 methyl-8-hydroxy-2,6-methano-3-benzazocine, 6.0 g. of 1-bromo-3-methyl-2-butene, ml. of N,N- dimethylformamide, and 5.0 g. of sodium bicarbonate was stirred and refluxed for approximately four and onehalf hours. The reaction mixture was then filtered, and the solid collected on the filter was washed with ethanol. The filtrate and the wash liquor were combined and concentrated under reduced pressure. To the resulting residue there was added 50 ml. of diethyl ether, and the mixture was filtered. Approximately 0.6 g. of solid was collected on the filter, and 8.2 g. of brown solid separated from the filtrate and was collected by filtration. These two crops of solid (8.8 g.) were combined, 25 ml. of methanol was added, and the mixture was boiled. Only a small portion of the solid dissolved. This mixture was mixed with 25 ml. of water and chilled. The mixture was filtered to collect 8.3 g. of pale tan solid which melted at 156l58 C. The product thus obtained was 1,2,3,4,5,6- hexahydro 3 (3-methyl-2-butenyl)-6-ethyl-l1-methyl-8- hydroxy-2,6-methano-3-benzazocine (Formula I:

- lar formula C H NO. The solubility of this product in a mixture of 0.34 ml. of N/ 2 hydrochloric acid and 19.66 ml. of water was less than 0.25 percent; and its solubility in ethanol was less than 1 percent (weight/volume).

B. Treatment of this base with diazomethane yields 1,2,3,4,5,6 hexahydro 3 (3 methyl 2 butenyl) 6- ethyl 1l methyl 8 methoxy 2,6 methano 3 benzazocine (Formula I: Z= CH CH=C(CH R =--CH R =CH and treatment of the base with acetic anhydride yields 1,2,3,4,5,6-hexahydro-3-(3-methyl- 2 butenyl) 6 ethyl 11 methyl 8 acetoxy 2,6- methano-3-benzazocine (Formula I:

Example 8. 1,2,3,4,5,6-hexahydr0-3-(Z-methyl-Z-prm penyl) 6,11 dimethyl 8 hydroxy 2,6 methano- S-benzazocine A. Using a procedure similar to that described in Example 4 hereinabove, 3.3 g. of l-chloro-2-methyl-2- propene was interacted with 7.5 g. of 1,2,3,4,5,6-hexahydro 6,11 dimethyl 8 hydroxy 2,6 methane 3- benzazocine to produce 1,2,3,4,5,6-hexahydro-3-(2-methyl 2 propenyl) 6,11 dimethyl 8 hydroxy 6- methan'o-3-benzazocine (Formula II:

R H) having the molecular formula C N N which was treated with hydrochloric acid to yield 3.6 g. of the corresponding hydrochloride in the form of offwhite crystals which melted at 26026l C. (dec.). The solubility of the hydrochloride in Water was less than 0.25 percent, and in ethanol was less than 1 percent weight/ volume) B. Treatment of the base with diazomethane yields l,2,3,4,5,6 hexahydro 3 (2 methyl 2 propenyl)- 6,1l dimethyl 8 methoxy 2,6 methanol 3 benz'azocine and with acetic anhydride yields 1,2,3,4,5,6-hexahydro 3 (2 methyl 2 propenyl) 6,11 dimethyl- 8-acetoxy-2,6-methano-3-benzazocine.

Compounds of this invention which were prepared as described in the foregoing examples were found to be antagonists of certain strong analgesics. Thus, when tested in rats by a modified DAmour-Smith test procedure and in dogs, they were found to be antagonists of the analgesic activity of morphine and meperidine. In this test procedure, when the compounds of this invention were administered prior to or simultaneously with administration of morphine or meperidine, the expected analgesic effect of the latter was decreased with increasing dosage levels of the former to a point Where no analgesic effeet was obtained. And when the new compounds were administered after the administration of morphine or meperidine, the analgesic etiect was diminished or terminated, depending on the dosage levels involved. For example representative compounds of this invention, each in the form of an aqueous solution of the lactic acid acidaddition salt, were administered subcutaneously to rats to determine the dosage level, in terms of Weight of antagonist per kilogram of body weight of the animal, which caused reduction of the analgesic effect of a 60 mg./ kg. dose of meperidine hydrochloride by approximately 50 percent or 15 mg./kg. dose of morphine sulfate, so that the analgesic eifect produced by the combination of the antagonist and the rneperidine hydrochloride or the morphine sulfate was substantially the same as the analgesic effect produced by a 30 mg./kg. dose of meperidine hydrochloride alone or 7.5 rug/kg. of morphine sulfate alone, respectively. The results thus obtained for the lactic acid acid-addition salt of each of the indicated compounds were as follows:

When tested as analgesics by conventional methods in mice and rats, the compounds of Formulas I and H gave negative results. In human subjects, however, the compounds of Formulas I and II are valuable and effective agents for producing analgesia when administered in the general range of about 10 to 500 mg. per 70 kg. of subject weight, the dosage depending of course on the particular compound, the mode of administration, and the like. The following clinical results which were obtained in human subjects are illustrative. For oral administra tion the free base form was used, and for parenteral (usually intramuscular) administration an aqueous solution of thelactate salt was used; the dosages are expressed in each instance in terms of milligrams of base per 70 kilograms of body weight of the human subject.

As an analgesic agent in humans, l,2,3,4,5,6-hexahydro 3 allyl 6 ethyl l1 methyl 8 hydroxy 2,6- methano-3-benzazocine, obtained as described in Example 1A above, is used orally at a dosage in the approximate range of 5-50 mg./ 70 kg. and is used parenterally at a dosage in the approximate range 2-10 mg./70 kg. For example, when this compound of Example 1A was administered to human subjects parenterally at doses of 5 mg./ kg. and mg./kg., effective and satisfactory analgesia was produced in the subjects. Parenterally in humans, 5 mg. of the compound of Example 1A is approximately equivalent to 10 mg. of morphine sulfate as an analgesic.

As an analgesic agent in humans, 1,2,3,4,5,6-hexahydro 3 (3 methyl 2 butenyl) 6,11 dimethyl 8- hydroxy-2,6-methano-3-benzazocine, obtained as described in Example 4A above, is used orally at a dosage in the approximate range 10500 mg./ 70 kg. and is used parenterally at a dosage in the approximate range 10- 350 mg./70 kg. For example, when this compound of Example 4A was administered to human subjects orally at doses of 50 mg./70 kg. and 100 rug/70 kg, and parenterally at 10 mg./ 70 kg. and 60 mg./ 70 kg., effective and satisfactory analgesia was produced in the subjects. Results in stabilized morphine addicts indicated that 1,2,3,4,5,6 hexahydro 3 (3 methyl 2 butenyl)- t v 6,11 dimethyl 8 hydroxy 2,6 methano 3 benzazocine did not support morphine addition in these addicts. Parenterally inhumans, 20 mg. of the compound of Example 4A is approximately equivalent to 10 mg. of morphine sulfate as an analgesic.

As an analgesic agent in humans, 1,2,3,4,5,6-hexahydro 3 (3 methyl 2 butenyl) 6 ethyl l1 methyl- 8-hydroxy-2,6-methano-3-benzazocine, obtained as described in Example 7A above, is used orally at a dosage in the approximate range 25-500 mg./70 kg. and is used parenterally at a dosage in the approximate range lO-lOO mg./7O kg. For example, when this compound of Ex ample 7A was administered to human subjects parenterally at doses of 10 mg./70 kg. to mg./70 kg., effective and satisfactory analgesia was produced in the subjects.

I claim;

1. The process for producing analgesia in a human subject which comprises administering to said human subject an analgesically effective amount of a 1,2,3,4,5,6- hexahydro 3 (Z) 6 (R l1-(R )-8-(R -O-) 2,6-methano-3-benzazocine having the formula 3. The process for producing analgesia in a human subject which comprises administering to said human subject an analgesically effective amount of a l,2,3,4,5,6- hexahydro 3 (B-methyl 2 butenyl) 6 ethyl- 11 methyl 8 hydroxy 2,6 methano 3 be'nzazocine having the formula NC Hg-O H=C (CH3): CHCH3 i CH2 c om Cal-I5 4. The process for producing analgesia in a human subject which comprises administering to said human subject an analgesically effective amount of a 1,2,3,4,5,6-

'hexahydro 3 (Y) 6,11 dimethyl 8 (R O 2,6-methano-3-benzazocine having the formula in which Y is lower alkenyl containing 4-6 carbon atoms and R is lower alkanoyl.

5. The process for producing analgesia in a human subject which comprises administering to said human subject an analgesically effective amount of 1,2,3,4,5,6-

13 hexahydro 3 (3 methyl 2 butenyl) 6,11- dimethyl 8 hydroxy 2,6 methano 3 benzazocine having the formula CH2CH 6. The process for producing analgesia in a human subject which comprises administering to said human subject an analgesically efi'ective amount of 1,2,3,4,5,6- hexahydro 3 (Z) 6 -(R )-11-(R 8 (H O 2,6-methano-3-benzazocine having the formula in which Z is lower alkenyl containing 3-6 carbon atoms; one of R and R is ethyl and the other is a member of the group consisting of hydrogen, methyl and ethyl.

14 8. The process for producing analgesia in a human subject which comprises administering to said human subject an analgesically effective amount of 1,2,3,4,5,6-

hexahydro 3 (Y) 6,11 dim'ethyl 8 (H O 2,6-methano-3-benzazocine having the formula CH2CH N-Y CHCH3 (IEH 11-0 \CCH2 in which Y is lower alkenyl containing 4-6 carbon atoms. 9. The process for producing analgesia in a human subject which comprises administering to said human subject an analgesically effective amount of 1,2,3,4,S,6- hexahydro 3 (Y) 6,11 dimethyl 8 (CH O 2,6-methano-3-benzazocine having the formula CH2C-H OHCH: CH3 O CH2 C C H:

in which Y is lower alkenyl containing 4-6 carbon atoms.

References Cited by the Examiner UNITED STATES PATENTS 2,955,073 IlO/ 1960 De Beer 167-65 2,959,594 11/ 1960 Gordon et al. 2-6O 294.3 2,986,573 5/1961 Topliss et al.. 167-65 3,033,867 5/ 1962 Gordon 260285 3,073,835 1/1963 Rorig 260-294.7

JULIAN S. LEVITT, Primary Examiner.

DUVAL MCCUTCHEN, FRANK CACCIAPAGLIA, 111., D. M. KERR, PAUL L. SABAT'INE, MARTIN J. COHEN, Assistant Examiners. 

1. THE PROCESS FOR PRODUCING ANALGESIA IN A HUMAN SUBJECT WHICH COMPRISES ADMINISTERING TO SAID HUMAN SUBJECT AN ANALEGESICALLY EFFECTIVE AMOUNT OF A 1,2,3,4,5,6HEXAHYDRO - 3 - (Z) - 6 - (R1) - 11 - (R2) - 8 - (R3- O - )2,6-METHANO-3-BENZAZOCINE HAVING THE FORMULA 